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| United States Patent |
5,717,005
|
|
Richardson
|
February 10, 1998
|
Adhesive compositions and products
Abstract
Chlorhexidine gluconate-containing adhesives have dispersed therein solid
chlorhexidiene particles which will pass through a 125 .mu.m sieve and at
least about 30% of the total volume of particles has a size of not less
than 5 .mu.m. The adhesive may be a vinyl ether adhesive and may be coated
upon a backing layer such as a hydrophilic polyurethane to produce
products suitable for use as wound dressings, IV dressing or incise
drapes. The chlorhexidine gluconate may be obtained as a freeze-dried
solid and added directly, in suspension, to the adhesive mass without
further milling.
| Inventors:
|
Richardson; Mark Christopher (Huby, GB)
|
| Assignee:
|
Smith & Nephew PLC (London, GB)
|
| Appl. No.:
|
167914 |
| Filed:
|
December 20, 1993 |
| PCT Filed:
|
June 19, 1992
|
| PCT NO:
|
PCT/GB92/01112
|
| 371 Date:
|
December 20, 1993
|
| 102(e) Date:
|
December 20, 1993
|
| PCT PUB.NO.:
|
WO93/00118 |
| PCT PUB. Date:
|
January 7, 1993 |
Foreign Application Priority Data
| Current U.S. Class: |
523/111; 424/448; 514/635; 514/772.4; 523/118; 528/905; 602/48; 602/52; 602/54; 604/307 |
| Intern'l Class: |
A61L 015/03; A61F 013/00 |
| Field of Search: |
523/111,118
424/448
514/635,772.4
602/48,52,54
604/307
528/905
|
References Cited
U.S. Patent Documents
| 5035687 | Jul., 1991 | Sandbank | 602/52.
|
| Foreign Patent Documents |
| 0011471 | May., 1980 | EP.
| |
| 0023395 | Feb., 1981 | EP.
| |
| 0065399 | Dec., 1982 | EP.
| |
| 0065370 | Dec., 1982 | EP.
| |
| 2186486 | Aug., 1987 | EP.
| |
| 0240097 | Oct., 1987 | EP.
| |
| 0256893 | Feb., 1988 | EP.
| |
| 9000066 | Jan., 1990 | WO | 602/54.
|
Other References
World Patents Index (Latest), Week 9016, AN.dbd.90-121106, Derwent
Publications Ltd., London, GB & JP,A2073013, 13 Mar. 1990.
|
Primary Examiner: Merriam; Andrew E C
Attorney, Agent or Firm: Larson & Taylor
Claims
I claim:
1. An adhesive composition, suitable for medical applications, comprising
an adhesive having dispersed therein 2-10% by weight, based on the weight
of the composition, of solid particles of chlorhexidine gluconate, wherein
said particles have a particle size of less than 125 .mu.m and at least
about 30% by volume of the particles have a particle size of not less than
5 .mu.m.
2. A composition as claimed in claim 1 wherein the adhesive is an acrylic
or polyvinyl ether based adhesive.
3. An adhesive product comprising a backing layer having coated thereon an
adhesive composition as defined in any one of the preceding claims.
4. A product as claimed in claim 3 which has a moisture vapor transmission
rate of at least 300 gm.sup.-2 24h.sup.-1 at 37.degree. C. and at a 100%
to 10% relative humidity difference when in contact with moisture vapor.
5. A product as claimed in claim 3 in which the backing layer is a flexible
material selected from knitted, woven or non-woven fabrics, nets,
microporous or continuous synthetic polymer films.
6. A product as claimed in claim 5 wherein the backing layer is a synthetic
polymer film comprising a polyurethane.
7. A product as claimed in claim 6 wherein the polyurethane comprises a
hydrophilic polyurethane which contains from 5 to 50% by weight of water
when hydrated.
8. A product as claimed in any of the claims 4 to 7 in the form of a wound
dressing for non-exuding wounds and having an adhesive thickness of up to
about 5 mm.
9. A product as claimed in any one of the claims 4 to 7 in the form of a
wound dressing for exuding wounds and having an adhesive thickness of up
to 25 mm.
10. A dressing pack containing a dressing as claimed in claim 9 in sterile
form and contained within a bacteria and water proof pouch.
11. A method of treating a wound on an animal by applying to the wound an
adhesive dressing as claimed in claim 9.
Description
This invention relates to adhesive compositions and to adhesive products.
More particularly, the invention relates to medicated adhesive
compositions and to products coated therewith.
Adhesive products containing a releasable medicament in the adhesive are
known. The advantage of having a medicament, such as an anti-bacterial
agent, in the adhesive is that the medicament is delivered to the site for
release and use when the adhesive is applied eg. as part of a wound
dressing. By providing a vehicle from which such medicaments as
anti-bacterial agents can be released in a sustained manner, the area can
be maintained free from bacterial infection. A known medicated adhesive
product containing an antibacterial agent is sold under the trade name
"OpSite CH" By T. J. Smith and Nephew Limited. The antibacterial
incorporated into the adhesive layer is chlorhexidine acetate.
Chlorhexidine gluconate is also a well known antibacterial agent. However,
because it is a extremely hygroscopic material its use is limited and in
many applications it can only be used as a 20% aqueous solution, which is
commercially available. In our researches we have found that it has only
been possible to use gluconate solutions in adhesive formulations in
amounts not exceeding about 3% by weight of chlorhexidine gluconate since
at levels much above this the tack properties of the adhesive are
adversely affected.
We have now found it possible to prepare chlorhexidine gluconate-containing
adhesive compositions having higher levels of anti-bacterial activity and
acceptable adhesive values then has been hitherto available.
Thus in accordance with the invention, there is provided an adhesive
composition, suitable for medical applications, comprising an adhesive
having dispersed therein solid particles of chlorhexidine gluconate,
wherein said particles have a particle size of less than 125 .mu.m and at
least about 30% by volume of the particles have a particle size of not
less than 5 .mu.m.
Particles used in the invention which have a particle size of less than 125
.mu.m are particles which will pass through a 125 .mu.m mesh screen.
The solid form of chlorhexidine gluconate may be obtained by freeze-drying
aqueous solutions of the gluconate, eg the commercially available 20%
aqueous solution. The particle size of the freeze dried material is
usually of a suitable size that the material requires no further
comminution prior to incorporation into the adhesive mass.
The adhesives used in the invention may be any of those medically
acceptable adhesives which are compatable with the gluconate. In
particular the adhesive material should not contain groupings, such as
free acid groups, which will react with the gluconate and thus render it
unavailable for release. Suitably, the adhesive is one which is
hydrophilic in nature.
Apt adhesives for use in the adhesive composition of the invention may
include acrylic adhesives and adhesives based on polyvinyl ethers. A
preferred acrylic adhesive is described in European Patent Publication No.
35399. A typical polyvinyl ether adhesive composition suitable for use in
the present invention is that described as adhesive composition A in UK
Patent specification No. 1280631.
The amount of chlorhexidine gluconate that is present in the adhesive can
range up to 10% by weight of the weight of the composition without
adversely affecting the tack of the adhesive. Thus amounts of
chlorhexidine gluconate can be included which would exhibit bactericidal
properties as well as bacteriostatic properties. Hitherto it has not been
possible to include more than about 3% by weight chlorhexidine gluconate,
as an aqueous solution, before the adhesive surface becomes deadened. At
such low levels the anti-bacterial activity is restricted to that of
bacteriostatic activity and with such adhesive compositions little or no
bactericidal activity is observed.
We have also found that, on a weight for weight basis, adhesives based on
solid gluconate have superior anti-bacterial properties than those
adhesives based on chlorhexidine gluconate in solution. Effective
bactericidal activity can be achieved at concentrations of from 2-3% by
weight.
In accordance with a further aspect of the invention there is provided a
process for the production of an adhesive composition which comprises
admixing particles of chlorhexidine gluconate with a medically acceptable
adhesive wherein the particles have a particle size of less than 125 .mu.m
and wherein at least about 30% by volume of the particles have a particle
size of not less than 5 .mu.m.
In a preferred embodiment of the process of the invention, freeze dried
particles of chlorhexidine gluconate are dispersed in a liquid which is a
non-solvent for the gluconate but a solvent for the adhesive. The liquid
may suitably be a non-polar liquid. Thus for a composition base on a
polyvinyl ether adhesive, a suitable solvent for the adhesive, which is a
non-solvent for chlorhexidine gluconate is petroleum ether, commercially
available is SBP2.
Dispersion of the particles can be achieved by conventional mixing
techniques such as high shear mixing. After formation of the dispersion
with the as-produced freeze dried chlorhexidine gluconate, the dispersion
may be filtered through a suitably sized mesh screen and the particles
caught on the screen recycled to the mixing zone.
We have found that by the choice of relatively large sizes of particles,
good adhesion values can be retained and yet good release properties of
the antibacterial can be achieved. If any significant comminution of the
as-produced freeze dried product takes place, the adhesive properties of
the composition are adversely affected.
The adhesive compositions of the invention are suitable for use in the
manufacture of adhesive products such as wound dressings, intra-venous
access site dressings (IV dressings) and surgical drapes.
Thus in accordance with another aspect of the present invention there is
provided an adhesive product comprising a backing layer having coating
thereon of a medically acceptable adhesive having dispersed therein solid
particles of chlorhexidine gluconate, wherein said particles have a
particle size of less than 125 .mu.m and at least about 30% by volume of
the particles have a particle size of not less than 5 .mu.m.
The backing layer employed in the adhesive products of the present
invention are desirably capable of conforming to the body contours when
applied to the skin and should be flexible enough to move with the body
without becoming detached. Suitable flexible backing materials include
knitted, woven or non-woven fabrics, nets, microporous films such as
plasticised polyvinyl chloride films, polymer blend films containing
voids, polymeric films, including thermoplastic polyurethane and
hydrophilic polyurethane, elastomeric polyesters, styrene-butadiene block
copolymers such as Kraton (Trade mark) thermoplastic rubbers.
Favored materials which may be used at the backing layer in the adhesive
product of the present invention include films of hydrophilic polymers.
Apt hydrophilic polymers include hydrophilic polyurethanes, polyvinyl
pyrrolidone, polyvinyl alcohol and cellulosic derivatives.
A favored hydrophilic polymer is a hydrophilic polyurethane. Suitable
hydrophilic polyurethanes include those having the composition and
prepared by the process described in British Patent No. 2093190B. The most
suitable hydrophilic polyurethanes are those which contain from 5 to 50%
by weight of water when hydrated, more suitably from 10 to 40% by weight
of water and which have a thickness when present in a dressing of from 25
to 120 .mu.m, more suitably 30 to 60 .mu.m. A preferred film of
hydrophilic polyurethane has a water content when hydrated of 20 to 30%
for example 25% and a thickness of up to 50 .mu.m for example 30 .mu.m.
A favored flexible backing material is a microporous plasticised polyvinyl
chloride film formed by the process disclosed in British Patent No.
884232. preferred microporous plasticised polyvinyl chloride films have a
thickness of from 100 to 300 .mu.m typically between 150 .mu.m and 250
.mu.m for example about 200 .mu.m.
A further favored backing layer is a film of thermoplastic polyurethane
including the linear polyester polyurethanes or polyether polyurethanes
known as Estanes (Trade mark). Such polyurethanes are used as films from
15 to 75 .mu.m in thickness, more favorably 20 to 35 .mu.m in thickness
for example about 25 .mu.m or 30 .mu.m.
The adhesive layer may vary in thickness depending upon the type of skin
lesion, wound or other similar use the dressing is to be put, that is
thinner layers up to about 5 mm may be used on non-exuding wounds or on
dressings for use at intravenous sites while thicker layers for example up
to 25 mm may be used on exuding wounds where the absorptive properties of
the adhesive may be advantageously used.
The adhesive products of the present invention may be prepared by casting
the backing layer from a solution of the appropriate polymer at a suitable
concentration onto a silicone release paper and removing the solvent to
give a film of the required thickness. A film of the adhesive composition
at the required thickness is prepared and the two films brought together
and adhered to each other to form a laminate, preferably without the use
of any further adhesives. Handles may be applied at any convenient stage
during the production of the dressing. Release coated protectors may be
placed over the adhesive layer or layers and the laminate cut into
dressings of the appropriate size for example 5 cm.times.5 cm, 7.5
cm.times.7.5 cm, 8 cm.times.8 cm, 10 cm.times.10 cm, 5 cm.times.10 cm and
10 cm.times.20 cm. The adhesive products, when used as wound dressings,
for example, may be packaged in a bacteria-proof and water-proof pouch and
be sterilized by conventional methods such as irradiation and ethylene
oxide.
In use the sterile dressing is removed from the pouch, the protector
removed from the adhesive surface of the dressing and the dressing is
applied to the wound.
Dressings in accordance with the invention may be used as a dressing for
wounds caused by physical or surgical trauma, burns, ulcers and the like,
as a surgical drape, as dressing for intravenous access sites and any
dressing for which long term attachment to the skin may be required.
In a further aspect therefore the present invention provides a method of
treating a wound on an animal body by applying to the wound an adhesive
dressing as hereinbefore described.
By a suitable choice of adhesive and/or backing layer, the adhesive
products of the invention may be rendered impervious to water, yet will
allow moisture vapor to pass therethrough. The rate at which moisture
vapor passes through the dressing is the moisture vapor transmission rate
(MVTR). The MVTR can be determined either with water in contact with the
dressing (the `inverted MVTR`) or in contact with water vapor alone
(`upright MVTR`).
A suitable method of determining the upright moisture vapor transmission
rate of the dressing of this invention is as follows. Discs of material
under test are clamped over Payne Permeability Cups (flanged metal cups)
using sealing rings and screw clamps. The exposed surface area of the test
sample may be conveniently 10 cm.sup.2. Each cup contains approximately 10
ml of distilled water. After weighing the cups are placed in a fan
assisted electric oven maintained at 37.+-.1.degree. C. The relative
humidity within the oven is maintained at 10% by placing 1 Kg of anhydrous
3-8 mesh calcium chloride on the floor of the oven. The cups are removed
after 24 hours, allowed to cool for 20 minutes and re-weighed. The MVTR of
the test material is calculated from the weight loss expressed in units of
grams of weight per square meter per 24 hours.
A suitable method of determining the inverted moisture vapor transmission
rate of the dressing of this invention is as follows. The method described
above is employed except that the Payne Cups are inverted in the oven so
that the water within the cups is in contact with the test material and in
this case with the adhesive.
Aptly adhesive products in accordance with the present invention will have
MVTR's in excess of 300 gm.sup.-2 and preferably greater than 500
gm.sup.-2, suitably more than 1200 gm.sup.-2. Inverted MVTR's are
preferably greater than upright MVTR's and are desirably greater than
about 1200 gm.sup.-2.
In a preferred aspect therefore the present invention provides an adhesive
product in the form of a wound dressing which includes backing material
comprising a hydrophilic polyurethane and a continuous layer of pressure
sensitive adhesive comprising an adhesive composition in accordance with
the invention and the product has a moisture vapor transmission rate of
between 1400 and 1600 gm.sup.-2 24h.sup.-2 at 37.degree. C. and 100 to 10%
relative humidity difference when the adhesive is in contact with moisture
vapor.
The present invention will be illustrated by the following example.
A slurry was prepared of freeze dried chlorhexidine gluconate in petroleum
ether (SBP2) using a high shear mixer. The concentration of the
chlorhexidine gluconate was 12.5% w/w.
A portion of the slurry was then pumped to a SUSSMEYER Bead Mill comprising
a 1.5 liter stainless steel shell filled with up to 99% volume of 1 mm
diameter lead-free glass beads. The milled slurry was passed through a 125
.mu.m sieve to remove any unmilled gluconate and any broken glass
particles. Particle size distribution analysis showed that almost all the
particles were below 16 .mu.m with 48% in the range 2-4 .mu.m.
A further portion of the slurry was passed directly through the 125 .mu.m
mesh sieve, without milling. Particle size analysis of this portion showed
that, again most of the particles were below 16 .mu.m. However a number of
particles were found in the 16 to 100 .mu.m range.
A vinyl ether adhesive was made as described for Composition A in UK Patent
Specification No. 1280631.
To one part of the adhesive was added the screened slurry of milled
chlorhexidine gluconate to a concentration of 5.3% by weight and to
another part of the adhesive was added the screened slurry of the unmilled
gluconate, again at a chlorhexidine gluconate concentration of 5.3%.
A third part of the adhesive was retained as a control and contained no
added chlorhexidine gluconate.
Each of the three adhesives were cast onto a 25 .mu.m thick polyurethane
film at a coating weight of 30 gm.sup.-2
Samples of each of the coated films were then subjected to ethylene oxide
sterilisation and thereafter tested for microbiological activity by the
IOBAN zone diffusion test against Staphloccocus aureus 10788 in comparison
with non-sterilized samples of each coated film. The bacterial counts were
made initially (0 mins) and after the lapse of 5 minutes. The results of
the IOBAN tests are reported below.
______________________________________
Mean Log.sub.10
Count/ml
Sterilising
Sample Time (mins)
Medicament condition 0 5
______________________________________
None (Control) 5.78 .+-. 0.01
5.80 .+-. 0.02
Un-milled Non-Sterile
5.89 .+-. 0.07
2.12 .+-. 0.05
Milled 5.83 .+-. 0.03
2.09 .+-. 0.53
None (Control) 5.93 .+-. 0.08
5.88 .+-. 0.06
Un-milled 5.90 .+-. 0.10
2.18 .+-. 0.80
Milled 5.76 .+-. 0.18
2.77 .+-. 0.01
______________________________________
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